Project Summary Impairments in new learning and memory are common in Multiple Sclerosis (MS) and negatively impact several aspects of everyday life, including occupational and social functioning. Despite the demand for learning and memory treatments few cognitive rehabilitation (CR) protocols to date are supported by Class I research evidence, thereby limiting the degree to which potentially efficacious treatments may be applied to MS. To address this critical need, the presently proposed randomized clinical trial (RCT) examines the efficacy of an 8-session CR protocol encompassing training in the application of three strategies (self-generation, spaced learning and self-testing) with the greatest empirical evidence to treat impaired learning and memory in persons with MS, Strategy-based Training to Enhance Memory (STEM). The currently proposed double-blind placebo-controlled randomized clinical trial (RCT) addresses a central objective highlighted in the NCMRR 2016 Research Plan by seeking to reduce ?symptoms and secondary conditions associated with disability through the development, adaptation or evaluation on interventions? (p. 1531). We will conduct a double-blind, placebo-controlled RCT, administering STEM to 120 participants with MS who evidence NLM deficits. Outcome will be assessed via 3 mechanisms, an Assessment of Global Functioning (AGF), which examines everyday functioning and quality of life, a Neuropsychological Evaluation (NPE) to examine objective cognitive performance, and neuroimaging to elucidate neural mechanisms of STEM and its mechanisms. The examination of daily life activities as an a priori endpoint in this RCT is a highly innovative aspect of the currently proposed work, highlighted as a significant gap in the rehabilitation literature by the NCMRR1. We will additionally evaluate the longer-term efficacy of STEM on everyday functioning and NPE through a 6-month follow-up evaluation and evaluate the impact of booster sessions in maintaining the treatment effect over time. Importantly, the rigorous research design employed in the current study is highly responsive to the objectives set forth by the NCMRR in their most recent research plan, to ?increase the quality of evidence for rehabilitation interventions ?through increased focus on the design?and outcomes of these interventions? (p. 152). Such ?evidence based approaches are essential for rehabilitation research? (NCMRR, 20162) Supported by strong preliminary data, this novel and innovative intervention has the potential to significantly remediate NLM deficits in persons with MS, ultimately leading to improved social and occupational functioning (i.e., participation) and overall QOL. Results of the current study will provide Class I evidence for the STEM treatment protocol for persons with MS due to the methodologically rigorous study design. Finally, the currently proposed work is well grounded in a long line of memory rehabilitation work at KF led by the current PI and represents the next systematic step in the line of work examining strategy training. 1. National Center for Medical Rehabilitation Research (NCMRR): Overview. https://www.nichd.nih.gov/about/org/ncmrr/Pages/overview.aspx. Accessed September 14, 2017. 2. The Eunice Kennedy Shiver National Institute of Child Health and Human Development and the NIH Medical Rehabilitation Coordinating Committee. National Institutes of Health (NIH) Rehabilitation Plan on Rehabilitation: Moving the Field Forward. 2016. Accessed September 14, 2017.